Abnormal accumulations of filamentous aggregates in neurons, glia or the extracellular space are neuropathological hallmarks of many sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (Lbs) formed by filamentous alpha-synuclein (AS) aggregates in neurons are characteristic of Parkinson's disease (PD), dementia with Lbs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while glial cytoplasmic inclusions (GCIs) composed of AS filaments are signature lesions of multiple system atrophy (MSA). The hypothesis that Lbs play a role in the degeneration of neurons was viewed with increasing skepticism until it was shown that mutations in the AS gene cause familial PD, that AS is a major component of Lbs and GCIs, and that mutant and wild type AS gene cause familial PD, that AS is a major component of Lbs and GCIs, and that mutant and wild type AS form LB-like filaments in vitro. Moreover, LBVAD (AD with DLB) is the most common subtype of sporadic AD, and AS positive Lbs are present in >60% of familial AD (FAD) brains as well as in >50% of Down's syndrome brains with AD. Finally, it has been shown that beta- (BS) and gamma-synucleins (GS) accumulate in dystrophic hippocampal processes in PD and DLB brains. Thus, we hypothesize that accumulations of synuclein filaments or aggregates play a mechanistic role in the onset/progression of neurodegenerative diseases characterized by abundant synuclein pathology (i.e., synucleinopathies). Aims 1-4 in Project 1 will test aspects of this hypothesis utilizing two approaches: by determining if LB and GCI filaments as well as dispersed AS filaments are comprised only of AS or if other proteins are integral filament components, and by examining the relationship of dispersed AS filaments to those in Lbs and GCIs. Aims 5 and 6 will test related aspects of this hypothesis by determining how Lbs and GCIs compromise the viability of affected neurons and glial cells, respectively. Insights into the underlying mechanisms of synuclein pathologies may lead to improved strategies for the diagnosis and treatment of synucleinopathies as well as other neurodegenerative disorders characterized by filamentous brain lesions.